Type II diabetes, also known as non-insulin-dependent diabetes mellitus or adult onset diabetes, is mainly where insulin secretion is too little in patients or the body cannot use insulin effectively (namely insulin resistance). Currently there are about 185 million diabetics around the world, in which type II diabetes accounts for about 90 to 95% of all diabetic patients, and it is growing at a rate of 6% per year. In 2010, the morbidity of type II diabetes has reached around 9.7% among Chinese adults over 20 years old.
Currently, therapies for type II diabetes include insulin secretagogues, such as sulphonylureas, which promote pancreatic 13 cells to produce more insulin; antidiabetic agents, such as metformin, which reduce the formation of glucose in the liver; activators of the peroxisome proliferator-activated receptor-γ (PPAR-γ), such as the thiazolidinediones, which improve insulin sensitivity and enhance the bioavailability of insulin; and α-glucosidase inhibitors, which interfere with glucose production in the gut. However, the current treatments of existing methods have certain deficiencies. For example, sulphonylureas and insulin injections can be associated with hypoglycemic episodes and weight gain. Furthermore, patients often lose response to sulphonylureas over time and produce tolerance. Metformin and α-glucosidase inhibitors often lead to gastrointestinal problems, and PPAR-γ agonists tend to cause weight gain and edema.
Research directed to several areas is ongoing in order to bring new, more effective antidiabetic drugs to the marketplace. For example, the present inventors are exploring ways to reduce excessive hepatic glucose production, enhance the transduction of the signal pathway of insulin-induced glucose uptake, improve glucose-stimulated insulin secretion (GSIS) in pancreatic β cells, and are studying obesity and fat metabolism, accumulation abnormalities, and the like.
Free fatty acids (FFA) play key roles in several aspects of metabolism. For example, they are the “priming,” which enhances the response of insulin of the pancreatic β cells to glucose in the fasting state, and they are the starting point for lipogenesis. Initially, GPR40 was found in an orphan receptor form from the human genome. GPR40 is highly expressed in pancreatic β cells and insulin-secreting cell lines. GPR40, also known as fatty acid receptor 1 (FFAR1), is a member of the gene superfamily of G-protein coupled receptors (“GPCRs”). GPCRs are membrane proteins having seven transmembrane domains, and can respond to a variety of molecules, thereby activating intracellular signaling transduction pathways, and are critical for achieving a variety of physiological functions. GPR40 activation is linked to regulation of the Gq family of intracellular signaling proteins and is accompanied with inducing the increase of calcium iron levels. GPR40 was the first fatty acid receptor to be identified on the cell surface, capable of binding the most common fatty acids in plasma such as palmitate, oleate, stearate, linoleate, and linolenate, etc. GPR40 could be considered as a ‘nutrient sensing’ receptor, playing several tissue-dependent roles, which may affect overall glucose utilization and/or fat metabolism. For example, long-chain FFAs amplify GSIS in pancreatic 13 cells through the activation of GPR40.
GPR40 regulators play an incretin effect to promote GSIS. Moreover, they can also be combined with various antidiabetic drugs. Based on the above, GPR40 agonists may be used for treating diabetes and associated conditions, particularly type II diabetes, obesity, glucose intolerance, insulin resistance, metabolic syndrome X, hyperlipidemia, hypercholesterolemia, atherosclerosis, neurodegenerative diseases (for example Alzheimer's disease), and other indications such as stroke. Taking GPR40 as a potential therapeutic target, a compound for finding and modifying GPR40 has a very important research value and application prospect.
Up to now, a series of GPR40 agonists has been disclosed by some patent applications, such as WO2005087710, WO2005051890, and WO2004106276 etc.
However, although a series of GPR40 agonists for the treatment of disorders such as diabetes and metabolic syndrome X, etc. were disclosed presently, there is still a need to develop new compounds with more effective activities. After continuous efforts, the present disclosure provides the compounds of fomula (I), and discovers that these compounds having such structures show better efficiency and function.